Clinical and experimental immunology最新文献

Prevention and treatment of infections are primary goals of treatment of children and adults with primary immune deficiencies due to decreased antibody production. Approaches to these goals include immunoglobulin replacement therapy, vaccination, and prophylactic treatment with antimicrobials. In this review, the infectious and non-infectious complications of antibody deficiencies will be discussed along with the limited number of studies that support the effective use of the available therapies and to drive the development of new therapies. Some illustrative case studies will be presented and the outlook for additional controlled clinical trials and potential for therapies driven by the underlying disease genetics will be considered.

Anti-Sjögren's syndrome type A (anti-SSA) antibodies are non-organ-specific autoantibodies highly prevalent in various autoimmune diseases. This study primarily investigated the prevalence of anti-SSA antibodies in the health screening population. Additionally, we explored the clinical features of the anti-SSA antibody-positive population and evaluated the development of connective tissue diseases (CTD) over the years in individuals with anti-SSA antibodies for whom follow-up was available. A total of, 64 045 individuals without a history of CTD from 2013 to 2022 who visited Peking Union Medical College Hospital for health screening were screened for autoimmune antibodies: 1.7% (1091/64 045) of the Chinese health screening population were positive for anti-SSA antibodies, with a prevalence of 0.9% (290/33 829) in men and 2.7% (801/30 216) in women. Compared with matched autoantibody-negative controls, anti-SSA antibody-positive individuals had higher levels of serological abnormalities, including erythrocyte sedimentation rate (ESR) [10 (6-15) mm/h vs. 7 (4-12) mm/h, P < 0.0001], rheumatoid factor (RF) [7.15 (4.30-16.90) IU/ml vs. 5.00 (3.20-7.90) IU/ml, P < 0.0001], and immunoglobulin G [13.09 (11.20-15.45) g/L vs. 11.34 (9.85-13.18) g/L, P < 0.0001], and lower levels of white blood cells (WBC; 5.49 ± 1.50 × 109/L vs. 5.82 ± 1.49 × 109/L, P < 0.0001). Additionally, they had a higher proportion of coexisting thyroid autoantibodies, including anti-thyroid peroxidase antibodies (TPO-Ab) (17.1% vs. 11.3%, P < 0.0001) and anti-thyroglobulin antibodies (Tg-Ab) (17.8% vs. 11.0%, P < 0.0001). Among the 381 subjects who were anti-SSA positive and followed up for a median of 4.6 years, 146 (38.3%) individuals developed CTD, including 68 (17.8%) cases of primary Sjögren's syndrome (pSS), 10 (2.6%) cases of rheumatoid arthritis (RA), 5 (1.3%) cases of systemic lupus erythematosus (SLE), 4 (1.0%) cases of secondary Sjögren's syndrome (sSS), and 59 (15.5%) cases of undifferentiated connective tissue disease (UCTD). In all, 235 (61.7%) individuals did not develop CTD over a median time of 5.9 (2.9-8.1) years after the earliest autoantibody detection. Elevated ESR (>20 mm/h), RF positivity (>20 IU/ml), and female gender were identified as independent risk factors for CTD among the anti-SSA antibody-positive individuals. Anti-SSA antibodies were found in 17 among approximately 1000 individuals without a history of autoimmune diseases. Anti-SSA antibody-positive individuals are advised to periodically monitor thyroid function. Elevated ESR (>20 mm/h), female gender, and RF positivity may delineate a high-risk cohort for CTDs.

Recently, the incidence of malignant tumors is on the rise and searching for new treatments on it has become the research priority. Blocking the vascular endothelial growth factor (VEGF) and its receptor (VEGFR) is one of the treatment strategies that used in the development of specific anti-angiogenic drugs. The deficiencies in tissue penetration and affinity maturation become the weakness of these drugs in anti-tumors applications. The single heavy chain antibody found in Chiloscyllium plagiosum, which has a low molecular weight and superior tissue penetration of variable region (variable new antigen receptor, VNARs), was considered to have the high antigen-binding activity and stability. This type of antibody has a simple structure that can be prokaryoticaly expressed, which makes it easily to produce new antiangiogenic target drugs. Specific anti-IgNAR rabbit multiple antibodies have been used to assess the level of VNARs in sharks and have shown a significant enrichment of IgNAR after triple immunization. An anti-VEGFR2 phage library was used for the targeted VNARs screening, and five candidate VNARs sequences were subsequently obtained by phage screening, followed by combined screening with the transcriptome library, and analysis of conserved regions along with 3D modelling matched the VNAR profile. ELISA and cell-based assays showed that two of the VNARs, VNAR-A6, and VNAR-E3, had a superior antigen affinity and anti-angiogenic activity thereby being able to inhibit human Umbilical Vein Endothelial Cells proliferation and migration. The anti-VEGFR2 VNARs derived from the immunized C. plagiosum and screened by phage library, which provide the new research ideas and specific approaches for the development of new drugs. The anti-VEGFR2 VNARs are capable for blocking the VEGF-VEGFR pathway, which of these may contribute to expanding the use of anti-angiogenic drugs.

Asthma exacerbation is a common clinical occurrence. The causal factors are not fully understood yet. Environmental pollution is linked to asthma exacerbation. The objective of this study is to elucidate the role of 3-methyl-4-nitrophenol (MNP), an environmental pollutant, in asthma exacerbation. In this study, an airway allergy mouse model was established with ovalbumin as a specific antigen with or without the presence of MNP. The results showed that, in a mouse model, the intensity of airway allergy was significantly increased by exposure to MNP. RNAseq results showed an increase in endoplasmic reticulum (ER) stress-associated molecules and the Osm expression in airway epithelial cells of mice with airway allergy. Exposure of epithelial cells to MNP in culture induced the expression of oncostatin M (OSM) and ER stress associated molecules. The OSM receptor was expressed by macrophages. OSM could drive macrophages to produce tumor necrosis factor-α (TNF-α). Inhibition of PERK, one of the key molecules of ER stress, or depletion of OSM receptor in macrophages, could effectively attenuate the MNP/ovalbumin protocol induced airway allergy. To sum up, by promoting ER stress, environmental pollutant MNP can cause airway epithelial cells to produce OSM. The latter induces macrophages to produce TNF-α, which can exacerbate airway allergy.

Mutations in the human nuclear factor-κB2 gene (NFKB2) are associated with common variable immunodeficiency (CVID) or combined immunodeficiency diseases (CID), characterized by B-cell lymphopenia, hypogammaglobulinemia, and T cell dysfunction. This study investigated whether B cells with NFKB2 mutations exhibit intrinsic impairments in activation, class-switch recombination, and differentiation. We analyzed five patients from four unrelated families with CVID, each carrying a heterozygous NFKB2 mutation: P1 (C.2595_2614del, p.A867Gfs*12), P2 (C.2597G>A, p.S866N), P3 (C.2540dupT, p.R848Efs*38), and P4 and P5 (C.2570_2571insCAGCACA, p.A860Qfs*28). The patients with frameshift mutations (P1, P3, P4, and P5) exhibited truncated proteins detectable in their peripheral blood mononuclear cells, while P2 had a missense mutation. All identified mutations disrupted the processing of p100 into the active p52 form, resulting in NF-κB2 loss-of-function and IκBδ gain-of-function. Clinically, P1, P2, and P3 exhibited B-cell lymphopenia, and all five patients presented with hypogammaglobulinemia. Notably, P2 exhibited a markedly low B-cell count, associated with increased proportions of memory B and IgD-CD27- double negative B cells. In vitro experiments with naïve B cells from P1 and P4 demonstrated decreased survival, impaired activation, and reduced differentiation into CD27+IgD- cells and plasmablasts, while class switch recombination was unaffected. These findings reveal novel B cell-intrinsic functional defects in patients with NFKB2 mutations.

Low titers to pneumococcal vaccine are a frequent finding in pediatric patients with recurrent oto-sinopulmonary infections. To characterize the pre- and post-immunization antibody trend for each serotype included in the pneumococcal 13-valent conjugate vaccine (PCV13), in a cohort of pediatric patients with recurrent oto-sinopulmonary infections. This retrospective review identified 182 patients with recurrent oto-sinopulmonary infections (131 required an immune workup and 99 had low pneumococcal titers leading to a PCV13 vaccine booster). Baseline pneumococcal serotype-specific antibody titers at initial visit and 6 weeks after the vaccine booster were obtained. An adequate response to the pneumococcal conjugate vaccine was deemed to be a 4-fold increase over baseline and/or a post-immunization titer of 1.3 µg/ml or greater. Overall, PCV13 booster provided a significant improvement in the number of protective titers, increasing from 3.6 serotypes at baseline to 11.1 serotypes at 6 weeks (p < 0.001). This increase correlated with improved clinical outcomes (81% showed no signs of recurrent infection after the first booster and 94% after a second booster). Post-immunization antibody concentrations were significantly higher than at baseline for all serotypes (p< 0.05) and only 8, 9N, and 12F did not exhibit a greater than 4-fold increase (p> 0.05) 6 weeks following booster. There were no differences between patients at different ages in post-immunization titer levels for all serotypes. In pediatric patients with recurrent oto-sinopulmonary infections, an additional pneumococcal booster proved to be effective in the protection of these children against further infections, across all age groups.

Ovarian cancer, with its high mortality rate among gynecological cancers, is often diagnosed late due to the lack of early diagnostic symptoms and biomarkers. The tumor immune microenvironment has become a focal point in cancer diagnostic and therapeutic research. Among these, B7-H4, a checkpoint protein, plays a crucial role in immune regulation and tumor suppression, contributing to immune evasion within the tumor microenvironment. This study aims to identify the concentration of soluble B7-H4(sB7-H4) in the plasma of patients with ovarian cancer and to evaluate its clinical significance. Through a comprehensive analysis involving enzyme-linked immunosorbent assay, immunohistochemistry, and multicolor immunofluorescence, we quantified sB7-H4 levels in patient plasma and ascites, correlating these findings with tissue expression and clinical outcomes. Results indicated a strong association between high sB7-H4 levels and advanced disease, surgical outcomes, lymphatic metastasis, and platinum resistance. When compared with traditional biomarkers CA125 and HE4, sB7-H4, especially in conjunction with these markers, enhances the diagnostic accuracy for epithelial ovarian cancer, offering insights into disease progression and therapeutic efficacy. This comprehensive analysis suggests that sB7-H4 is a promising biomarker for EOC, providing valuable insights into diagnosis, stage differentiation, treatment effectiveness, and prognosis.

Inborn errors of immunity (IEI) are a large heterogenous group of diseases characterized by immunodeficiency, immune dysregulation, allergy, auto-inflammation and predisposition for malignancies. Most are inherited in an autosomal recessive trait. We studied a patient with severe combined immunodeficiency (SCID) and immune dysregulation who harbored two distinct bi-allelic IEI-associated genetic mutations. Clinical, immunological and genetic data were collected. Genetic investigation included whole exome sequencing on DNA extracted from skin fibroblasts. Family segregation was performed by Sanger sequencing. Immunological evaluation included absolute and functional evaluation of lymphocytes and chimerism analysis post hematopoietic stem cell transplantation (HSCT). Treg subsets, LRBA and CTLA4 expression levels were measured by flow-cytometric analysis. A nineteen-year-old female patient from a consanguine background underwent unconditioned matched sibling related HSCT during infancy due to clinical presentation of SCID with an Omenn phenotype. At that time her underlying genetic defect was not defined. Years after HSCT, severe auto-immune phenomena were noted, including a systemic lupus erythematosus-like syndrome and ophthalmic manifestations. Genetic evaluation revealed bi-allelic homozygous mutations in RAG-2 (c.685C>T, p.Arg229Trp) and a previously undescribed mutation in LRBA (c.3325G>T, p.Asp1109Tyr). LRBA and CTLA4 expression levels were normal, suggesting that the LRBA variant identified in these kindred is unlikely to be pathogenic. Multiple genetic defects causing complex IEIs may be identified in the same individual in highly consanguineous populations. Functional immunological testing is essential for evaluation of novel genetic variants.

Members of the T-cell immunoglobulin and mucin (TIM) family, which is crucial for T-cell function, are implicated in autoimmunity. TIM-1 and -3 play distinct roles in autoimmunity, with TIM-1 acting as a costimulatory molecule and TIM-3 regulating Th1 responses. We investigated the therapeutic potential of anti-TIM-1 (RMT1-10) and anti-TIM-3 (RMT3-23) antibodies in an autoimmune arthritis model. Zymosan A was used to induce arthritis in female SKG mice. The arthritis scores, histology, mRNA expression, cytokine levels, micro-computed tomography, and flow cytometry results were obtained. The application of RMT1-10 reduced the arthritis scores, histological damage, and CD4+ T-cell infiltrations, and it suppressed interleukin (IL)-6 and -17A and reduced TIM-3 mRNA expressions. RMT3-23 also lowered arthritis severity, improved histology, and reduced serum levels of tumor necrosis factor (TNF)-α and IL-17A. RMT3-23 inhibited intracellular TNF-α and IL-6 and early apoptosis. An amelioration of autoimmune arthritis was achieved by blocking the TIM-1 and -3 signaling pathways via RMT1-10 and RMT3-23 administration, leading to a widespread decrease in inflammatory cytokines. Both antibodies exhibited therapeutic effects, suggesting TIM-1 and -3 as potential targets for rheumatoid arthritis.